Celecoxib is a non-steroidal anti-inflammatory drug (NSAID) used in the treatment of osteoarthritis, rheumatoid arthritis, acute pain, painful menstruation and menstrual symptoms and to reduce the number of colon and rectum polyps in subjects with familial adenomatous polyposis. It has additionally been demonstrated that celecoxib may reduce the incidence of certain cancers such as colon cancer, ultraviolet B radiation-induced skin cancer, oral cancer (Sood et al., 2005) and breast cancer (Kawamori et al., 1998; Fischer et al., 1999; and Harris et al., 2000).
Celecoxib functions by specifically inhibiting the enzyme cyclooxygenase-2 (COX-2). There are two forms of COX, namely COX-1 and COX-2, and both enzymes bring about the conversion of arachidonic acid to prostaglandin (PG), a local mediator involved in the generation of biological responses such as pain, fever and inflammatory symptoms. However, COX-2 expression is induced under inflammatory conditions, whereas COX-1 is constitutively expressed in healthy tissues in physiological (normal) processes (Kujubu et al., 1991; Masferrer et al., 1992; Siebert et al., 1994; and Xie et al., 1991). In contrast to specific COX-2 inhibitors such as celecoxib, conventional NSAIDs non-selectively inhibit both COX-1 and COX-2. Inhibiting physiological (COX-1 mediated) production of prostaglandins inhibits gastroduodenal mucosal defence, the renal system and platelet aggregation (Fischer et al., 1999; Fulton, 1984; Narisawa et al., 1983; Pentland et al., 1999; and Reddy et al., 1993), and long term use of such conventional NSAIDs is accordingly associated with significant side effects.
When delivered orally to achieve systemic therapy, celecoxib can be used to treat the symptoms of pain and inflammation without side-effects on the gastric tract, renal system or platelets, symptoms that are associated with conventional NSAIDs. It can alternatively be delivered topically for treatment of osteoarthritis, rheumatoid arthritis, and the treatment and prevention of colorectal and oral cancers, amongst other conditions.
However, celecoxib is considered difficult to formulate because of its chemical properties. It exists in three polymorphic forms, is weakly acidic, hydrophobic (log P≈3.5), and classified as having low solubility (7 μg/ml) and, accordingly, has low bioavailability. It does, however, have a high “Tmax” (that is, the time necessary to achieve maximal drug concentration in circulation) of approximately three hours after oral delivery. This means that the material that is bioavailable is well absorbed by the gut and readily enters into circulation; however, as the bioavailability is low, absorption is incomplete and variable. Further, this is considered to be a slow onset of action for pain relief. Celecoxib is also considered difficult to process into solid dosage forms.
Various systems have been developed to improve solubility of active substances, such as celecoxib, that are difficult to formulate. Some of these systems are also capable of mediating the effective delivery of active substances to target areas. An example of such a system is an encapsulated emulsion.
Emulsions are dispersed systems consisting of two immiscible liquids, one of which is dispersed (the dispersed or discontinuous phase) in a continuous phase, as droplets. If the droplets are oil-based droplets, then the emulsion can solubilise or complex amphiphilic or lipophilic active substances, whereas, if the droplets are aqueous, then water-soluble active substances can be entrapped. The dispersed droplets may comprise or include a suitably soluble substance, for example an active substance such as a drug compound; the dispersed droplets thereby acting as delivery vehicles.
To improve droplet stability in pharmaceutical applications, where the vehicles are used under physiological conditions, droplets can be encapsulated with a protective coating, producing encapsulated droplets known as capsules. The present invention is directed to the provision of capsules of this kind that are particularly well suited to use with celecoxib and like compounds, show good levels of droplet stability in physiological conditions and over time (ie in storage), appear to enhance the delivery of the active substance (ie relative to Celebrex® formulation, a currently marketed formulation of celecoxib), and which may, in turn, enhance the bioavailability of the active substance.